This application is a competitive renewal of an R01 completing its first cycle. The overall goal is to use in vivo magnetic resonance diffusion imaging (dMRI) to study white matter (WM) pathology in schizophrenia (SZ). Measurement of microstructural WM pathology has the potential to have a huge impact on new SZ treatment strategies (anti-inflammatory drugs, drugs promoting cell regeneration, myelin protective medication, etc.) The previous project cycle was focused on diffusion tensor imaging (DTI) and high angular resolution diffusion imaging (HARDI) models, and established that there are subtle abnormalities in the WM in SZ. In this new proposal we plan to develop more sensitive probes of tissue microstructure using advanced dMRI scanning and analysis techniques, to help explore the nature of the subtle abnormalities and pinpoint specific micro- pathology. The proposed advances in dMRI include development of methods for multiple-shell imaging to en- able measurement of the full 3D diffusion function (the propagator), and implementation of the recently developed double pulsed field gradient (double-PFG) sequence on a clinical scanner. These technologies will in- crease the scan time but will provide more specific information about tissue microstructure, increasing the sensitivity to brain changes and abnormalities. To make both double-PFG and multiple-shell measurements feasi- ble in clinical time, we propose to employ compressed sensing, an advanced sampling and reconstruction strategy that allows reconstruction of the image data with considerably fewer data points than are traditionally required. We will develop novel quantitative analysis methods, with special focus on analysis of the unique data produced by the double-PFG sequence. This type of data has not yet been investigated in clinical studies. Finally we will scan patients with schizophrenia and normal controls with the proposed protocols and apply the analysis methods to study group differences. We expect that upon successful completion of this project, we will have developed a clinically feasible dMRI paradigm including scanning and analysis pipelines that will help identify and quantify subtle changes in diffusion induced by pathology, which cannot be detected with current technology. PUBLIC HEALTH RELEVANCE: The overall goal is to use in vivo magnetic resonance diffusion imaging (dMRI) to study white matter (WM) pathology in schizophrenia (SZ). The proposed advances in dMRI include development of methods for multiple- shell imaging to enable measurement of the full diffusion function, and implementation of the recently developed double pulsed field gradient (double-PFG) sequence on a clinical scanner. We will scan patients with schizophrenia and normal controls with the proposed protocols and apply the analysis methods to detect cellular alterations in the WM in SZ.